Population Pharmacokinetics and Pharmacodynamics of the Therapeutic and Adverse Effects of Ketamine in Patients With Treatment‐Refractory Depression

Abstract

We aimed to develop population pharmacokinetic/pharmacodynamic (PK/PD) models that can effectively describe ketamine and norketamine PK/PD relationships for Montgomery–Åsberg Depression Rating Scale (MADRS) scores, blood pressure (BP), and heart rate (HR) following i.v., s.c., and i.m. ketamine administration in patients with treatment‐refractory depression. Ketamine PK/PD data were collected from 21 treatment‐refractory depressed participants who received ketamine (dose titration 0.1–0.5 mg/kg as single doses) by i.v., s.c., or i.m. administration. Model development used nonlinear mixed effect modeling. Ketamine and norketamine PK were best described using two‐compartment models with first‐order absorption after s.c. and i.m. administration. Estimated ketamine bioavailability after i.m. and s.c. was ~ 64% with indistinguishable first‐order absorption rate constants. Allometric scaling of body weight on all clearance and volumes of distribution improved the model fit. The delay in the concentration‐response relationship for MADRS scores was best described using a turnover model (turnover time ~ 42 hours), whereas for the BP and HR rates this was an immediate effect model. For all PD effects, ketamine alone was superior to models with norketamine concentration linked to an effect. No covariates were identified for PD effects. The estimated half‐maximal effective concentration from the MADRS score, BP, and HR were 0.44, 468, and 7,580 ng/mL, respectively. The integrated population models were able to effectively describe the PK/PD relationships for MADRS scores, BP, and HR after i.v., s.c., and i.m. ketamine administration. These findings allow for a deeper understanding of the complex relationships between route of ketamine administration and clinical response and safety.

Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial

“…First, the original dosing protocol was changed on the advice of the Data Safety Monitoring Board based on results of the first 51 completers, owing to lack of efficacy. Data indicating the bioavailability of subcutaneous ketamine to be about 0.66 were not available when the present study was designed, 25 and they suggest that 0.75 mg/kg subcutaneously is required to approximate 0.5 mg/kg given by intravenous infusion, which was shown to be effective in prior trials. 3 Although this mid-study adjustment provided useful insights on two approaches to dosing, it meant that neither cohort achieved the originally planned sample size.…”

Evidence for the beneficial effect of ketamine in the treatment of patients with post-traumatic stress disorder: A systematic review and meta-analysis

“…The dosing scheme by intravenous route presents dose with 1.5-2 mg/kg over 30-60 sec; however, may administer incremental doses of 0.5-2 mg/kg IV by 5-15 min; to oral route the dose 6-10 mg/kg PO once; mix with 0.2-0.3 mL/kg of a beverage, however, for resistant depression or PTSD symptoms were used infusion with 0.5 mg/kg IV twice weekly. 34 Must recently, the esketamine, the S-enantiomer of ketamine, was demonstrated good results by intranasal administrations, with Figure 3. Judgments about each methodological quality of clinical studies included in the review.…”

Use of ketamine for treatment resistant depression: updated review of literature and practical applications to a community ketamine program in Edmonton, Alberta, Canada

“…Ketamine may be administered in a variety of different routes, including IV, IM, subcutaneous (SC), IN, SL, and oral (PO), but each has different rates of bioavailability ( Table 1 ) and pharmacokinetics ( 84 , 85 ). Clinically, these differences may affect efficacy and tolerability.…”